Treatment and survival of patients diagnosed with high-risk HR+/HER2− breast cancer in the Netherlands: a population-based retrospective cohort study

Background Several factors may increase the risk of recurrence of patients diagnosed with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC). We aim to determine the proportion of patients with high-risk HR+/HER2− BC within the total HR+/HER2− BC cohort and compare their systemic treatments and survival rates with those of patients with low- and intermediate-risk HR+/HER2− BC and triple-negative (TN) BC. Patients and methods Women diagnosed with nonmetastatic invasive HR+/HER2− BC and TNBC in the Netherlands between 2011 and 2019 were identified from the Netherlands Cancer Registry. Patients with HR+/HER2− BC were categorised according to risk profile, defined by nodal status, tumour size, and histological grade. High-risk HR+/HER2− BC was defined by either four or more positive lymph nodes or one to three positive lymph nodes with a tumour size of ≥5 cm or a histological grade 3 tumour. Overall survival (OS) and relative survival (RS) were calculated using the Kaplan–Meier and Pohar–Perme method. Results In this study of 87 455 patients with HR+/HER2− BC, 44 078 (50%) patients were diagnosed with low risk, 28 452 (33%) with intermediate risk, and 11 285 (13%) with high-risk HR+/HER2− BC. In 3640 (4%) patients, the risk profile could not be defined. Endocrine therapy and chemotherapy were used in 38% and 7% of low-risk, 90% and 47% of intermediate-risk, and 94% and 73% of high-risk patients, respectively. The 10-year OS and RS rates were 84.1% [95% confidence interval (95% CI) 83.5% to 84.7%] and 98.7% (95% CI 97.3% to 99.4%) in low-risk, 75.1% (95% CI 74.2% to 76.0%) and 91.7% (95% CI 89.7% to 93.3%) in intermediate-risk, and 63.4% (95% CI 62.0% to 64.7%) and 72.3% (70.1% to 74.3%) in high-risk patients. The 10-year OS and RS rates of 12 689 patients with TNBC were 69.7% (95% CI 68.6% to 70.8%) and 79.1% (95% CI 77.0% to 80.9%), respectively. Conclusion The poor prognosis of patients with high-risk HR+/HER2− BC highlights the need for a better acknowledgement of this subgroup and supports ongoing clinical trials aimed at optimising systemic therapy.

The pathological tumour size was used when available.In patients with unknown pathological tumour size as well as patients who received neoadjuvant systemic therapy, the clinical tumour size was used when more advanced than the pathological tumour size.
b Tumours were considered node-positive based on either the clinical or pathological nodal status.The number of positive lymph nodes was based on the pathological nodal status.In clinically node-positive patients who received neoadjuvant systemic therapy, the positivity of one to three lymph nodes was assumed when more advanced than the pathological nodal status.c In patients aged younger than 35 years, node-negative tumours were considered intermediate-risk when having the following features: -Grade 1 tumour of more than 2 cm in size; -Grade 2 tumour of more than 1 cm in size.Abbreviations: ALND = axillary lymph node dissection; ER = oestrogen receptor; MARI = marking axillary lymph nodes with radioactive iodine 125 I seeds; PR = progesterone receptor; SNP = sentinel node procedure; TNM = tumour node metastasis.
Percentages may not add up to 100% because of rounding.
a Tumours were categorised according to the TNM classification of malignant tumours which was valid at the time of diagnosis, since only minor differences were present between the 7 th or 8 th edition.The pathological TNM stage was used when available.In patients with unknown pathological TNM stage as well as patients who received neoadjuvant systemic therapy, the clinical TNM stage was used.Abbreviations: ALND = axillary lymph node dissection; ER = oestrogen receptor; MARI = marking axillary lymph nodes with radioactive iodine 125 I seeds; PR = progesterone receptor; SNP = sentinel node procedure; TNM = tumour node metastasis.
Percentages may not add up to 100% because of rounding.
a Tumours were categorised according to the TNM classification of malignant tumours which was valid at the time of diagnosis, since only minor differences were present between the 7 th or 8 th edition.The pathological TNM stage was used when available.In patients with unknown pathological TNM stage as well as patients who received neoadjuvant systemic therapy, the clinical TNM stage was used.Abbreviations: CI = confidence interval; HR = hazard ratio; HR+ = hormone receptor-positive.

Table 2 .
Baseline characteristics of patients diagnosed with and surgically treated for non-metastatic invasive HR+/HER2-breast cancer in the Netherlands between 2011 and 2019 by period of diagnosis (N (%)) Supplementary Figure 1.Flowchart of included patients 12,696 patients surgically treated for nonmetastatic triple-negative breast cancer 7 men excluded 12,689 women surgically treated for nonmetastatic triple-negative breast cancer Supplementary

Table 3 .
Supplementary Figure2.Number and proportion of patients diagnosed with and surgically treated for non-metastatic invasive HR+/HER2breast cancer in the Netherlands between 2011 and 2019 according to risk profile, total and per 3-year incidence period Baseline characteristics of patients diagnosed with high-risk HR+/HER2-breast cancer by period of diagnosis (N (%))

Table 4 .
Systemic treatment choices in patients diagnosed with high-risk HR+/HER2-breast cancer by period of diagnosis (N (%)) Overall survival (A) and relative survival (B) of all patients diagnosed with and surgically treated for non-metastatic invasive HR+/HER2-breast cancer from date of diagnosis, per 3-year incidence period Supplementary

Table 5 .
Univariable and multivariable analyses of overall survival in all patients diagnosed with HR+/HER2-breast cancer